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Last updated: 8/1/2024
Years published: 2024
NORD gratefully acknowledges Caroline Crain, MD Candidate, McGovern Medical School, Kate Richardson, MS, CGC and Hope Northrup, MD, Department of Pediatrics, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth) and Children’s Memorial Hermann Hospital, for the preparation of this report.
Summary
DNM1-related epilepsy and neurodevelopmental disorder is a rare, genetic condition that affects the way the brain works. People with this condition can have a range of manifestations and common symptoms include epilepsy (seizures), autism and difficulty learning and thinking (intellectual disability) that may range from mild to profound. Many people with DNM1-related neurodevelopment disorder have symptoms that start in early childhood with seizures or walking and/or talking later than peers (developmental delay). However, some individuals with milder symptoms may start having seizures later in adolescence or never have seizures at all. Seizures are often difficult to treat (refractory epilepsy).
DNM1-related epilepsy and neurodevelopmental disorder is caused by a genetic change (variant) in the DNM1 gene and follows autosomal dominant inheritance. It is also known as “autosomal dominant developmental and epileptic encephalopathy 31A”
When there are variants in both copies of the DNM1 gene the condition is known as “developmental and epileptic encephalopathy-31B” which follows autosomal recessive inheritance.
Currently, there is not a cure for this genetic condition. However, certain therapies may help manage symptoms of the disorder. Seizures may be managed with anti-epileptic medications or dietary changes. Individuals with related autism or intellectual disability may benefit from supportive therapies like applied behavioral analysis therapy (ABA) as well as physical, speech and occupational therapy. As we learn more about genetic disorders, there remains a possibility of more tailored treatment and management of this condition.
Introduction
Though individuals have likely been affected by DNM1-related epilepsy and neurodevelopmental disorder for a long time, the gene was only discovered as a cause of the disorder in 2014.
DNM1-related neurodevelopmental disorder has variable expressivity, meaning there is a range of symptoms that can occur in people affected with the condition.
Reported signs and symptoms may include:
Individuals with a milder presentation may have autism and intellectual/developmental disabilities with or without seizures. If seizures develop, they could develop at later stages in life, such as adolescence.
Autosomal recessive developmental and epileptic encephalopathy 31B is characterized by the following signs and symptoms, usually beginning within the first few months after birth:
The average lifespan of someone with DNM1-related epilepsy and neurodevelopmental disorder is unknown given how rare this condition is. However, adequate management of symptoms is likely to lead to an increased quality of life.
DNM1-related epilepsy and neurodevelopmental disorder is caused by a genetic change (disease-causing variant) in the DNM1 gene. Genes are the body’s instruction manual for creating proteins that play critical roles in the body.
DNM1 is a gene that leads to the creation of the protein, dynamin1. This protein is important for managing the brain’s messaging system and is very important for proper brain development. Brain cells (neurons) communicate with one another via chemicals called neurotransmitters. When neurotransmitters are released from a neuron, they must be taken back up (recycled) to be used again. These neurotransmitters are released and then recycled in a container called a vesicle. Dynamin1 is important for ensuring that neurotransmitters can be taken back up into a neuron. Its exact role is to help the neurotransmitter’s container (vesicle) get back into the cell. When these containers cannot get back into the cell, neurons cannot communicate with one another as they typically should. The medical problems that occur in DNM1-related epilepsy and neurodevelopmental disorder happen because there’s not enough of the dynamin1 being made to do its job in the body.
Many different variants of the DNM1 gene can lead to this condition. As new variants are reported, we are learning more about how individuals may be affected differently based on the specific type of DNM1 variant that they have. Variants in certain parts of the gene (such as the GTPase or middle domains) are thought to cause a more severe presentation, while some variants may cause a milder disorder. Over time, more will be learned about how variants in the DNM1 gene change a person’s neurodevelopment and which symptoms they can cause.
When only one copy of the DNM1 gene is altered, DNM1-related epilepsy and neurodevelopmental disorder follows autosomal dominant inheritance, and it is known as “developmental and epileptic encephalopathy-31A”. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. Most of the genetic changes (variants) in this gene are “de novo,” meaning that it occurred for the first time in the affected individual and was not passed down from either biological parent. Rarely, this condition can be passed down to children from an affected individual. The risk of passing the variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
Inheritance of developmental and epileptic encephalopathy 31B (DEE31B) is autosomal recessive. This means that the disorder is inherited from both parents, who each carry one copy of a disease-causing gene variant but usually do not show symptoms.
DNM1-related epilepsy and neurodevelopmental disorder affects people of all backgrounds. There does not appear to be any increased risk for individuals of particular ethnic backgrounds. Males and females are equally affected. The prevalence of this condition is unknown, though it is thought to be very rare. Age of onset is typically in infancy.
DNM1-related epilepsy and neurodevelopmental disorder is diagnosed by genetic testing. Since many disorders may cause similar symptoms, it is important to confirm the diagnosis with the identification of a disease-causing genetic change (likely pathogenic or pathogenic variant) in DNM1. Individuals with seizures, developmental disability or autism should be referred to a genetic specialist for evaluation and testing.
Treatment is based on the medical problems that are present in an affected person to improve an individual’s quality of life. A multidisciplinary team of pediatricians, physicians who specialize in the diagnosis and treatment of neurological disorders (neurologists), speech pathologists, physical therapists and other healthcare professionals can be involved in care.
Management can include:
There are individual reports published of levetiracetam, a ketogenic diet, and cannabidiol causing worsening seizures in some individuals with DNM1-related epilepsy and neurodevelopmental disorder. Medication choice should be discussed with a neurologist.
Due to the rarity of the disease, there are no treatment trials that have been tested in a large group of patients. There are no standardized treatment protocols or guidelines for affected individuals.
Family members of affected individuals may consider genetic counseling to assess whether there is an increased risk of DNM1-related epilepsy and neurodevelopmental disorder in family members or future children. Individuals with DNM1-related epilepsy and neurodevelopmental disorder who are considering children should also seek genetic counseling to discuss their reproductive options. Psychosocial support for the entire family is essential as well.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
http://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Afsar T, Huang X, Shah AA, et al. Truncated DNM1 variant underlines developmental delay and epileptic encephalopathy. Front Pediatr. 2023;11: eCollection 2023.
Kim J, Teng LY, Shaker B, et al. Genotypes and phenotypes of DNM1 encephalopathy. J Med Genet. 2023;60(11):1076-1083.
Mei D, Parrini E, Bianchini C, Ricci ML, Guerrini R. Autism and mild epilepsy associated with a de novo missense pathogenic variant in the GTPase effector domain of DNM1. Am J Med Genet C Semin Med Genet. 2023; In press.
Motta M, Consentino MC, Fontana A, et al. DNM1 gene and its related epileptic phenotypes. J Pediatr Neurol. 2023;21(4):273-282.
AlTassan R, AlQudairy H, Alromayan R, et al. Clinical, radiological, and genetic characterization of a patient with a novel homoallelic loss-of-function variant in DNM1. Genes (Basel). 2022;13(12):2252.
Yigit G, Sheffer R, Daana M, et al. Loss-of-function variants in DNM1 cause a specific form of developmental and epileptic encephalopathy only in biallelic state. J Med Genet. 2022;59(6):549-553.
Choi E, Dale B, RamachandranNair R, Ejaz R. Pathogenic DNM1 gene variant presenting with unusually nonsevere neurodevelopmental phenotype: a case report. Neurol Genet. 2021;7(5)
Li H, Fang F, Xu M, et al. Clinical assessments and EEG analyses of encephalopathies associated with dynamin-1 mutation. Front Pharmacol. 2019;10:1454.
Brereton E, Fassi E, Araujo GC, et al. Mutations in the PH Domain of DNM1 are associated with a nonepileptic phenotype characterized by developmental delay and neurobehavioral abnormalities. Mol Genet Genomic Med. 2018;6(2):294-300.
Von Spiczak S, Helbig KL, Shinde DN, et al. DNM1 encephalopathy: a new disease of vesicle fission. Neurology. 2017;89(4):385-394.
Appenzeller S, Balling R, Barisic N, et al. De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am J Hum Genet. 2014;95(4):360-370.
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